Cocaine abuse/dependence remains a major social and public health problem. There are a significant number of cocaine dependent individuals for whom current behavioral treatment interventions are ineffective. Finding a successful pharmacological treatment for cocaine abuse/dependence continues to be an important yet elusive goal. Several compounds have been shown in pre-clinical studies to attenuate the discriminative stimulus and reinforcing effects of intravenous cocaine but when these medications have been tested in clinical trials, none have proven effective. It is not clear whether the lack of concordance is a function of the behavioral procedures that are used in these models or to a species difference. One strategy to answer this question is to conduct similar studies in humans to assess the validity of the animal models. Although there are established methods for studying the subjective, physiological, and reinforcing effects of intravenous cocaine in humans, drug discrimination methods with intravenous cocaine have not been developed. The potential advantage of studying the discriminative stimulus effects of drugs is that this procedure is particularly well suited for studying mechanisms underlying the dependence-related effects of drugs and has the potential to be relatively efficient, allowing several candidate medications to be evaluated over a relatively short period of time. The goal of this application is to establish the validity of an intravenous cocaine discrimination paradigm in humans. In the first study, human participants will be trained to discriminate the effects of intravenous cocaine injections. Dose-response functions will then be generated with cocaine doses higher and lower than the training dose and generalization tests will be conducted with doses of a drug similar pharmacologically to cocaine (d-amphetamine) and a drug different from cocaine (pentobarbital) to determine the specificity of the paradigm. The second study will determine whether oral cocaine can attenuate the subjective, physiological, and discriminative stimulus effects of intravenous cocaine injections. Although oral cocaine would be an unlikely medication for cocaine dependence, studies of the reinforcing effects of cocaine have demonstrated that they are blocked following the administration of oral cocaine and that this approach functions as a proof of concept in the absence of established blocking agents. These studies as a whole will investigate a promising new strategy for developing treatment medications for cocaine abuse/dependence. If successful, this will be an efficient paradigm for examining the ability of compounds to attenuate the effects of cocaine in humans and may lead to a successful pharmacological treatment for cocaine abuse/dependence.